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Identification of a LIF-responsive replication-competent human β cell

ABSTRACT: The beta (β) cell mass formed during embryogenesis is amplified by cell replication that occurs primarily during fetal and early postnatal development. Thereafter, β cells become functionally mature and their mass is maintained by a very low rate of replication. For those few β cells that replicate in adult life, it is not known how replication is initiated, uncoupled from β cell function nor whether this occurs in a specialized subset of β cells. To explore these issues with the aim of controlling replication of mature human β cells, we capitalized on a YAP overexpression system that induces cell cycle re-entry in stem cell derived-β cells. Singe cell RNA sequencing revealed an upregulation of components of the leukemia inhibitory factor (LIF) pathway upon cell cycle re-entry. Experimental activation of the LIF pathway induces replication and expansion of human stem cell derived- and adult β cells in vitro and in vivo. In both stem cell derived- and adult human β cells, the expression of the LIF receptor LIFR is restricted to a subset of β cells with distinct transcriptional profiles and defines a subpopulation of β cells with increased replication rates. Further analysis identified 15 transcription factors whose gene networks are active in replicating β cells. Overall, this study sheds light on regulatory networks that control β cell replication and reveals a heterogeneity in LIF responsiveness and replication competence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137961 | GEO | 2019/09/25

REPOSITORIES: GEO

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